Coxiella burnetii is the intracellular bacterial agent of human Q fever, a debilitating flu-like illness that can also present as severe chronic endocarditis. C. burnetii is spread by contaminated aerosols and targets alveolar phagocytes in vivo, where the pathogen actively regulates vesicular trafficking to establish a phagolysosome-like parasitophorous vacuole (PV) in which to replicate. Although PV biogenesis is critical for infection, the macrophage innate immune response to infection is not fully understood. The current proposal uses two novel infection models, human lung tissue and alveolar macrophages, to test the hypothesis that C. burnetii specifically alters human alveolar macrophage physiology to prevent inflammasome activity and avoid the innate immune response. These models will provide human-specific information not obtainable using current animal models. Aim 1 will characterize C. burnetii infection of lung cells, definitively proving the cell type targeted during human infection. Aim 2 will define macrophage inflammasome activation in response to avirulent C. burnetii and identify mechanisms by which virulent organisms avoid detection. Collectively, these studies will provide enhanced modeling of the C. burnetii infectious process and the human innate immune response to pulmonary pathogens.